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Guanylate binding proteins promote caspase-11-dependent pyroptosis in response to cytoplasmic LPS

Danielle M Pilla1, Jon A Hagar, Arun K Haldar

  • 1Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, NC 27710.

Proceedings of the National Academy of Sciences of the United States of America
|April 10, 2014
PubMed

Insights

Guanylate binding proteins (Gbp) activate caspase-11-dependent pyroptosis, a cell-autonomous immunity, against intracellular bacteria. Gbp(chr3) proteins are crucial for detecting cytoplasmic LPS and initiating this immune response.

Area of Science:

  • Immunology
  • Cell Biology
  • Microbiology

Background:

  • Interferon (IFN) receptor signaling triggers cell-autonomous immunity against intracellular bacterial pathogens.
  • Caspase-11 activation and pyroptosis are key components of the host defense against Gram-negative bacteria accessing the host cell cytosol.
  • The precise sensor for cytoplasmic LPS and inflammasome components remain incompletely defined.

Purpose of the Study:

  • To investigate the role of IFN-inducible guanylate binding proteins (Gbp) in caspase-11-dependent cell-autonomous immunity.
  • To determine if Gbp proteins are involved in the detection of cytoplasmic LPS and the activation of the noncanonical inflammasome.

Main Methods:

  • Utilized IFN-activated macrophages infected with Legionella pneumophila.
  • Investigated pyroptosis induction in wild-type and Gbp(chr3)-deficient macrophages.
  • Assessed pyroptosis triggered by purified cytoplasmic LPS from Salmonella.

Main Results:

  • IFN-inducible Gbp proteins, specifically Gbp(chr3), are essential for triggering caspase-11-dependent pyroptosis in response to cytoplasmic LPS.
  • Gbp(chr3) is required for pyroptosis induction by both intracellular L. pneumophila and purified cytoplasmic LPS from Salmonella.
  • Gbp(chr3)-deficient macrophages exhibited diminished pyroptosis upon challenge with cytoplasmic LPS.

Conclusions:

  • Gbp(chr3) proteins play a critical role in sensing cytoplasmic LPS, acting as key components in the activation of the noncanonical inflammasome.
  • These findings elucidate a novel mechanism of cell-autonomous immunity mediated by Gbp proteins against bacterial pathogens with cytosolic access.
Keywords:
Nos2cell deathimmunity-related GTPasesinterferon

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